This book presents the evidence related to the use of injectable biologics to provide faster and better healing for musculoskeletal lesions and conditions. The authors discuss approaches, such as blood derivatives and cell concentrates, applied to lesions of muscles, ligaments, tendons, bones, meniscus and cartilage, as well as osteoarthritis. Chapters are written by some of the most influential opinion leaders in the field, with up-to-date review of the current literature, where the authors explore both the potential and the limitations of these minimally invasive and promising treatments.
The first section is devoted to the formulations and rationale for the use of injectable orthobiologics, while the second section reviews current treatment methods applied to specific joints and pathologies – ranging from tendinopathies through non-unions to articular degenerative processes – as well as the results of these treatment approaches. The third section explores future perspectives, such as pluripotent stem cells, gene therapy, and the stimulation of intrinsic stromal cell niches. Appealing to a broad readership, this book will be of interest to both laboratory research scientists and clinicians, including orthopedists, sports physicians, physiatrists, and regenerative medicine experts.
Author(s): Giuseppe Filardo, Bert R. Mandelbaum, George F. Muschler, Scott A. Rodeo, Norimasa Nakamura
Publisher: Springer
Year: 2021
Language: English
Pages: 393
City: Cham
Preface
Contents
Part I: Injectable Orthobiologics: Formulations and Rationale
1: The Stem and Progenitor Cell Paradigms and Engineering Principles Guiding the Clinical Use of Cells or Cell-Derived Products for Regenerative Medicine
1.1 Overview
1.2 Domains of Progress
1.2.1 Choice between Rapid Point of Care Processing and Cell Expansion
1.3 Conceptual Paradigm of Stem and Progenitor Biology in the Context of Regenerative Medicine: Cell Composition and Cellular Kinetics
1.3.1 Stem and Progenitor Cell Systems and Niches
1.3.2 Tissue-Specific Kinetics and Stem/Progenitor Populations
1.3.3 Tissue-Derived Cell Populations: Heterogeneous Mixes of Cells and Biological Potential
1.3.4 Tissue-Specific Connective Tissue Progenitors
1.4 Engineering Principles
1.4.1 Clinical Assessment Measurement
1.4.2 Defining the Cellular Product and Process
1.4.3 Cell Composition
1.4.4 Analytical Method for Cell Composition Analysis
1.4.5 Sampling Bias
1.4.6 Defining and Documenting the Process
1.4.7 Defining the Efficacy of Processes and Process Steps
1.5 Conclusion
Glossary of Terms
References
2: Bone Marrow as a Source of Cells for Musculoskeletal Cellular Therapies
2.1 Introduction
2.2 Bone Marrow as a Cell Source
2.3 Clinical Rationale for Bone Marrow-Derived Cells in Cellular Therapy
2.4 Bone Marrow Aspiration Technique
2.5 Aspirate Yield, Composition, and Efficiency
2.6 Processing Options for BMA
2.7 Standardized Measurement and Report of BMA Dose and Composition
2.8 Putting it all Together
References
3: Adipose-Derived Stem/Stromal Cells, Stromal Vascular Fraction, and Microfragmented Adipose Tissue
3.1 Introduction
3.2 Adipose-Derived Stem/Stromal Cells and Adipose-Derived Products: Two Sides of the Same Moon
3.2.1 SVF and Microfat
3.2.2 Culture-Expanded Adipose-Derived Stem Cells (ASCs)
3.3 Influence of Patient-Specific Factors on Adipose-Derived Cells and Products
3.4 The Rationale for Using Injections of Culture-Expanded ASCs or Adipose-Derived Products
3.4.1 Paracrine Potential (Soluble Mediators and Exosomes/Microvesicles)
3.5 In Vitro and Preclinical Findings
3.5.1 Focus on Culture-Expanded ASCs and SVF/Microfat in Joint Degeneration
3.5.2 Focus on Culture-Expanded ASCs and SVF/Microfat in Tendon Repair
3.5.3 Focus on Culture-Expanded ASCs and SVF/Microfat in Bone Repair
3.5.4 Focus on Culture-Expanded ASCs and SVF/Microfat in Muscle Repair
3.6 Conclusions
References
4: Injections of Synovial Mesenchymal Stromal Cells
4.1 Introduction
4.2 Generation of MSCs Starting with Heterogeneous Mixtures of Colony-Forming Progenitors from Synovial Tissues
4.3 In Vitro Chondrogenic Potential of Synovial MSCs
4.4 Culture of MSCs with Autologous Serum
4.5 Intra-Articular Injections of Synovial MSCs in a Rat OA Model
4.6 Localization of Synovial MSCs after Injection
4.7 Properties of Synovial MSCs after Migration to the Synovium
4.8 Species-Specific Gene Expression Analysis
4.9 Mechanism by which Injections of Synovial MSCs Delay OA Progression
4.10 Clinical Study of Synovial MSC Injections into OA Knees
4.11 Conclusions
References
5: Placenta, Umbilical Cord, and Umbilical Cord Blood-Derived Cultured Stromal Cells
5.1 Structure and Function of the Placenta, Umbilical Cord, and Umbilical Vessels
5.2 Placenta-Derived Stromal Cells
5.2.1 Formulation
5.2.1.1 Collection
5.2.1.2 Isolation and Expansion
5.2.2 In Vitro and in Vivo Effects
5.3 Umbilical Cord-Derived Stromal Cells
5.3.1 Formulation
5.3.1.1 Collection
5.3.1.2 Isolation and Expansion
5.3.2 In Vitro and in Vivo Effects
5.4 Umbilical Cord Blood-Derived Stromal Cells
5.4.1 Formulation
5.4.1.1 Collection
5.4.1.2 Isolation and Expansion
5.4.2 In Vitro and in Vivo Effects
5.5 Conclusions
References
6: Injectable Allogenic Mesenchymal Stromal Cells: Advantages, Disadvantages, and Challenges
6.1 Introduction
6.2 Theoretical Advantages of Allogeneic MSCs
6.3 Theoretical Disadvantages of Allogeneic MSCs
6.4 Challenges for the Future
6.5 Conclusions
References
7: Injection of Steroid Hormones
7.1 Introduction
7.2 Corticosteroids in Orthopaedics
7.3 Side Effects
7.4 AAS Physiology
7.5 The Effects of AAS on Musculoskeletal Tissues
7.6 AAS Applications in the Treatment of Human Disease
7.7 AAS in Orthopaedics (Table 7.1)
7.7.1 Rotator Cuff Repair
7.7.2 Anterior Cruciate Ligament Reconstruction
7.7.3 Patellar Tendon
7.7.4 Total Knee Arthroplasty
7.7.5 Hip Fractures
7.8 Potential Side Effects
7.9 Future Directions
7.10 Conclusion
References
8: Intra-articular Hyaluronic Acid Injections
8.1 HA Chemistry and Structure
8.2 Current Product Profile
8.3 Biologic Effects of HA
8.4 Mechanical Effects of HA
8.4.1 Viscosity
8.4.2 Lubrication
8.5 Future Directions
8.6 Conclusion
References
9: Cytokines, Chemokines, Alpha-2-Macroglobulin, Growth Factors
9.1 Cytokines
9.1.1 Introduction
9.1.2 What Is Currently Available Clinically?
9.1.3 What Has Shown Promise in Preclinical Studies?
9.1.4 Future Directions
9.2 Chemokines
9.2.1 Introduction
9.2.2 What Is Currently Available Clinically?
9.2.3 What Has Shown Promise in Preclinical Studies?
9.2.4 Future Directions
9.3 Alpha-2-Macroglobulin
9.3.1 Introduction
9.3.2 What Is Currently Available Clinically?
9.3.3 What Has Shown Promise in Preclinical Studies?
9.3.4 Future Directions
9.4 Growth Factors
9.4.1 Introduction
9.4.2 What Is Currently Available Clinically?
9.4.3 What Has Shown Promise in Preclinical Studies?
9.4.4 Future Directions
9.5 Conclusions
References
10: Platelet-Rich Plasma: Processing and Composition
10.1 Introduction
10.2 Processing
10.2.1 Whole Blood
10.2.2 Anticoagulant
10.2.3 Isolation and Concentration Method
10.2.4 Activation
10.3 Product Composition
10.3.1 Growth Factors
10.3.2 Leukocytes
10.4 Conclusion
References
11: Placental Tissue Extracts
11.1 Introduction
11.2 Clinically Relevant Anatomy
11.3 Evidence in Sports Medicine
11.3.1 Cartilage Injury and Osteoarthritis
11.3.1.1 Basic Science
11.3.1.2 Human Studies
11.3.2 Tendon Injury
11.3.2.1 Basic Science
11.3.2.2 Human Studies
11.3.3 Ligament Injury
11.3.3.1 Basic Science
11.3.3.2 Human Studies
11.3.4 Plantar Fasciitis
11.3.4.1 Basic Science
11.3.4.2 Human Studies
11.4 Conclusion
References
12: Secretome, Extracellular Vesicles, Exosomes
12.1 Introduction
12.2 Composition of the Secretome and Its Extracellular Vesicle Fraction
12.2.1 Secretome: Preclinical and Clinical Evidence
12.2.2 Extracellular Vesicles: Preclinical and Clinical Evidence
12.3 Conclusions
References
Part II: Injectable Orthobiologics: Methods and Results Based on Anatomy and Pathology
13: Rotator Cuff Tendinopathy: Cell Therapy
13.1 Introduction
13.2 Rotator Cuff: From Mechanical to Biological Improvement
13.2.1 Early History
13.2.2 Biological Enhancement of Rotator Cuff Repair
13.3 The Theoretical Benefits of Cell Transplantation on Enthesis Healing
13.3.1 Reparative Process of the Enthesis
13.3.2 Rationale for the Use of Cells to Treat Tendon Disorders
13.3.3 Preclinical Studies
13.4 Benefit of Cell Transplantation for Rotator Cuff Repair: What Is the Current Evidence?
13.4.1 The First Trial: The Experience of the Senior Author
13.4.2 The Other Seven Trials
13.5 Conclusion
References
14: Rotator Cuff Tendinopathy: Biologics
14.1 Introduction
14.2 Platelet-Rich Plasma (PRP)
14.3 Hyaluronic Acid (HA)
14.4 Cytokines and Growth Factors
14.5 Conclusions
References
15: Orthobiologics for the Treatment of Tennis Elbow
15.1 Introduction
15.2 Pathophysiology
15.3 Evaluation of Tennis Elbow: Lateral Epicondylitis
15.4 Orthobiologic Treatment Options
15.4.1 Basic Mechanism of Action
15.4.2 Sites of Harvests and Source Materials
15.4.3 Biologic Selection
15.5 Clinical Results
15.5.1 PRP
15.5.2 Bone Marrow Aspirate (BMA) or Bone Marrow Aspirate Concentrate (BMAC)
15.5.3 Adipose Tissue-Derived Cells
15.5.4 Autologous Culture-Expanded Fibroblasts
15.5.5 Gold-Induced Cytokines Injection (Autologous Conditioned Serum)
15.6 Delivery of Orthobiologics
15.7 Conclusion
References
16: Patellar Tendinopathy: Cell Therapy
16.1 Introduction
16.2 Current Treatments
16.3 Cell Therapy
16.4 In Vitro Isolation and Preparation of Culture-Expanded Cell Populations with Potential Value in Treating Tendinopathy
16.5 Preclinical In Vivo Evidence for Cellular Therapy for Tendinopathy
16.6 Clinical Evidence for Cellular Therapy for Patellar Tendinopathy
16.7 Conclusions
References
17: Patellar Tendinopathy: Biologics
17.1 Introduction
17.2 Evaluation and Diagnostic Workup
17.3 Treatment Options
17.3.1 Nonoperative Management
17.4 Surgical Treatment
17.5 Role of Injectable Biologics
17.5.1 Overview
17.5.2 Number of Injections
17.6 PRP Formulations
17.7 Conclusion
References
18: Orthobiologics for the Treatment of Achilles Tendinopathy
18.1 Introduction
18.2 Pathophysiology
18.3 Role of Biologic Therapies
18.4 Corticosteroids
18.5 Sodium Hyaluronate
18.6 Platelet-Rich Plasma
18.7 Autologous Blood Products
18.8 Peripheral Blood Mononuclear Cells
18.9 Bone Marrow Aspirate and Bone Marrow Aspirate Concentrate
18.10 Processing of Adipose Tissue as a Cellular Preparation
18.11 Culture-Expanded Mesenchymal Stromal Cells
18.12 Culture-Expanded Adipose-Derived Stromal Cells (ADSCs)
18.13 Growth Factors
18.13.1 Transforming Growth Factor-β
18.13.2 Vascular Endothelial Growth Factor
18.13.3 Bone Morphogenetic Proteins (BMPs)
18.13.4 Interleukin-6 (IL-6)
18.13.5 Combination Treatment with Growth Factors
18.14 Proteinase Inhibitors
18.15 Conclusions
References
19: Orthobiologics for the Treatment of Plantar Fasciitis
19.1 Introduction
19.2 Platelet-Rich Plasma (PRP)
19.3 AWB vs PRP
19.4 Corticosteroid vs PRP
19.5 Prolotherapy
19.6 Bone Marrow Aspirate Concentrate (BMAC)
19.7 Placenta Tissue Extracts
19.8 Conclusions
References
20: Ligament Lesions: Cell Therapy
20.1 Introduction
20.1.1 Native Ligament Healing
20.1.2 Relevant Osseous and Soft Tissue Anatomy
20.1.3 Differences in Healing Between the Collateral Ligaments and Cruciate Ligaments
20.2 Types of Cellular Therapies
20.3 Outcomes and Reasons for Cell Therapy
20.3.1 Cell Therapies for Anterior Cruciate Ligament
20.3.1.1 Preclinical Evidence
20.3.1.2 Clinical Evidence
20.3.2 Cell Therapies for Collateral Ligaments
20.3.2.1 Preclinical Evidence
20.3.2.2 Clinical Evidence
20.3.3 Cell Therapies for Ulnar Collateral Ligament
20.4 Current Indications and Contraindications
20.5 Conclusions
References
21: Ligament Lesions: Biologics
21.1 Introduction
21.2 PRP Use in Anterior Cruciate Ligament Injuries
21.3 PRP Use in Medial Collateral Ligament Injuries
21.4 PRP Use in Ankle Sprains
21.5 Conclusion
21.6 Summary Table
References
22: Meniscal Lesions: Cell Therapy
22.1 Introduction
22.2 Cell Selection
22.3 Mechanism(S) of Action of MSCs
22.4 Preclinical Studies
22.5 Clinical Studies
22.6 Future Directions
22.7 Conclusion
References
23: Meniscal Lesions: Biologics
23.1 Introduction
23.2 The Management of Meniscal Lesions
23.3 The Rationale of Orthobiologics Injections
23.4 Corticosteroid Injections
23.5 Hyaluronic Acid Injections
23.6 Platelet-Rich Plasma Injections
23.7 Conclusions
References
24: Orthobiologics for the Treatment of Muscle Lesions
24.1 Introduction
24.2 Muscle Injuries
24.2.1 Epidemiology and Mechanism of Injury
24.2.2 Muscle Lesions: Classification
24.2.3 Treatment Strategies and Burdens
24.3 Healing Process of Muscle Injuries
24.4 Platelet-Rich Plasma (PRP) in Muscle Injury
24.4.1 PRP: Biological Rationale and Formulations
24.4.2 PRP: Clinical Evidence
24.5 Other Biological Approaches
24.5.1 Culture-Expanded Stromal Cell Therapy
24.5.2 Glycosaminoglycans
24.5.3 Anti-Fibrotic Therapy
24.5.4 Actovegin
24.6 Conclusions
References
25: Cartilage Lesions and Osteoarthritis: Cell Therapy
25.1 Introduction
25.2 Osteoarthritis (OA)
25.3 Cell Therapies for Repair of Cartilage Lesions and OA Damage
25.4 Mesenchymal Stromal Cells (MSCs)
25.5 MSCs and the Immune System
25.6 Clinical Studies of MSC Injection
25.7 Lessons from Preclinical Animal Studies
25.8 One-Step Approaches
25.8.1 Bone Marrow Aspirate Concentrate (BMAC)
25.8.2 Stromal Vascular Fraction (SVF) and Micro-Fragment Adipose Tissue (MFAT)
25.9 Conclusions
References
26: Cartilage Lesions and Osteoarthritis of the Knee: Biologics
26.1 Introduction
26.2 Clinical Evidence
26.2.1 Corticosteroids
26.2.2 Hyaluronic Acid
26.2.3 Platelet-Rich Plasma
26.3 Conclusions
References
27: Cartilage Lesions and Osteoarthritis of the Hip and Ankle: Orthobiologics
27.1 Introduction
27.2 State of the Art of the Injective Therapies in the Hip
27.2.1 Hyaluronic Acid
27.2.2 Platelet-Rich Plasma
27.2.3 Cell-Based Therapies
27.3 State of the Art of the Injective Therapies in the Ankle
27.3.1 Hyaluronic Acid
27.3.2 Platelet-Rich Plasma
27.3.3 Cell-Based Therapy
27.4 Conclusions
References
28: Injectable Orthobiologics for the Treatment of Subchondral Insufficiency Fractures of the Knee (SIFK) and Related Pathogenic Processes
28.1 Introduction
28.2 Etiology and Pathogenesis
28.2.1 Pathophysiology
28.2.2 Role of Demographic Risk Factors
28.2.3 Role of Anatomic Risk Factors
28.2.4 Role of Procedural Risk Factors
28.3 Injectable Orthobiologic Treatments
28.3.1 Calcium Phosphate
28.3.2 Bone Marrow Aspirate Concentrate (BMAC)
28.3.3 Platelet-Rich Plasma (PRP)
28.3.4 Other Biological Approaches
28.4 Conclusions
References
29: Injections: Orthobiologics and the Power of Placebo
29.1 Introduction: A Historical Note on the “Placebo Effect”
29.2 Mechanisms of the Placebo Effect
29.3 Placebo and Musculoskeletal Injections
29.4 Conclusions
References
Part III: Future Directions
30: Pluripotent Stem Cells: Embryonic/Fetal Stem Cells and Induced Pluripotent Stem Cells
30.1 Introduction
30.2 Generation of iPSCs
30.2.1 Methods Used to Reprogram Somatic Cells into iPSCs
30.2.2 Epigenetic Signature of iPSCs
30.3 Induction of Chondrogenesis from iPSCs
30.3.1 Co-Culture with Primary Chondrocytes
30.3.2 Via Embryoid Body Formation
30.3.3 Through Intermediate iMSC
30.3.4 Direct Differentiation Using Growth Factors
30.4 The Use of iPSCs for Cartilage Regeneration
30.5 Strategy for Clinical Application: iPSC Banking
30.6 Direct Conversion to Chondrocytes Without the Need for iPSCs
30.7 Conclusions
References
31: Gene Therapy
31.1 Introduction
31.2 Gene Therapy: Principles
31.3 Injectable Gene Therapy for Musculoskeletal Applications
31.3.1 Cartilage Repair
31.3.2 Bone Healing
31.3.3 Tendon and Ligament Healing
31.3.4 Meniscal Repair
31.4 Perspectives
31.5 Conclusion
References
32: In Situ Targeting of Stem and Progenitor Cells in Native Tissues
32.1 Introduction
32.2 Mobilization of Stem/Progenitor Cells
32.3 Homing of Stem/Progenitor Cells into Sites of Tissue Repair and Regeneration
32.4 Differentiation of Stem/Progenitor Cells
32.5 Conclusions
References
